Clinical Applications of Noncoding RNAs in Cancer

Clinical Applications of Noncoding RNAs in Cancer summarizes the existing strategies, advances, and future opportunities on the role of noncoding RNAs in cancer patients. Established clinicians and researchers from all around the world share their views and expertise and provide readers with invaluable knowledge on the subject.

This book provides a comprehensive collection of information on the utility of noncoding RNAs in the diagnosis, prognosis, and therapy of cancer. It also discusses the evolutionary significance of noncoding RNAs and how the molecular tools such as RNA-seq, RNA-FISH, ic-SHAPE, and quantitative real-time PCR help in the detection and elucidation of the functions of noncoding RNAs. Additionally, the challenges associated with noncoding RNA approaches and future developments are discussed.

It is a valuable resource for cancer researchers, oncologists, clinicians, and other biomedical field members who want to learn more about noninvasive ways to diagnose and efficiently treat diverse cancer types.

• Presents a beginning chapter summary to help readers understand the content thoroughly
• Encompasses detailed description of information from clinical studies on noncoding RNAs in cancer therapy
• Discusses one cancer type per chapter making the content easy to reference

• Language: English
• Publisher: Academic Press
• Release date: Jan 19, 2022
• ISBN: 9780128245514

Book preview

Clinical Applications of Noncoding RNAs in Cancer

Edited by

Subash Chandra Gupta

Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India

Kishore B. Challagundla

Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States

Table of Contents

Cover image

Title page

Copyright

List of contributors

Preface

Chapter 1. Noncoding ribonucleic acid for pancreatic cancer therapy

Abstract

1.1 Introduction

1.2 Experimental methods and tools for analyzing noncoding RNAs in pancreatic cancer patients

1.3 Bioinformatics for analyzing noncoding RNAs in pancreatic cancer patients

1.4 Noncoding RNA

1.5 Pancreatic cancer–specific microRNAs

1.6 Pancreatic cancer–associated lncRNAs

1.7 Pancreatic cancer–associated circular RNAs

1.8 Diagnostic microRNA markers of PDAC

1.9 Diagnostic lncRNA markers of PDAC

1.10 Diagnostic circular RNA markers of PDAC

1.11 Summary and conclusion

Acknowledgment

References

Chapter 2. Applications of noncoding RNAs in brain cancer patients

Abstract

2.1 Introduction

2.2 Data sets for noncoding RNAs analysis

2.3 Expression of noncoding RNAs in brain cancer patients

2.4 Experimental methods and tools for analyzing noncoding RNAs in brain cancer patients

2.5 Noncoding RNAs as predictive marker for brain cancer patients

2.6 Potential of noncoding RNAs in predicting chemoresistance and radioresistance in brain cancer patients

2.7 Therapeutic potential and targeting of ncRNAs in brain cancer patients—challenges and perspectives

2.8 Summary and conclusions

References

Chapter 3. Noncoding RNAs in patients with colorectal cancer

Abstract

3.1 Introduction

3.2 Experimental methods and tools for analyzing noncoding RNAs in colorectal cancer patients

3.3 Microarray

3.4 Serial analysis of gene expression

3.5 Cap analysis gene expression

3.6 RNA sequencing

3.7 Dataset and bioinformatics for analyzing noncoding RNAs in colorectal cancer patients

3.8 Expression of noncoding RNAs in colorectal cancer patients

3.9 Sample types used for analyzing noncoding RNAs

3.10 Cell signaling pathways modulated by noncoding RNAs in colorectal cancer patients

3.11 Several other mechanisms

3.12 Clinical applications of noncoding RNAs as biomarkers in patients with colorectal cancer

3.13 Diagnostic potential of noncoding RNAs in colorectal cancer patients

3.14 Prognostic potential of noncoding RNAs in colorectal cancer patients

3.15 Therapeutic potential of noncoding RNAs in colorectal cancer patients

3.16 Potential of noncoding RNAs in predicting chemoresistance and radioresistance in colorectal cancer patients

3.17 Conclusion

References

Chapter 4. Applications of noncoding ribonucleic acids in multiple myeloma patients

Abstract

4.1 Introduction

4.2 Samples and experimental methods for the analysis of noncoding RNAs in multiple myeloma patients

4.3 Datasets analyzing noncoding RNAs in multiple myeloma patients

4.4 Noncoding RNAs implicated in the etiology of multiple myeloma

4.5 Cell signaling pathways modulated by noncoding RNAs in multiple myeloma

4.6 Noncoding RNAs affecting interactions with the bone marrow niche

4.7 Noncoding RNAs as diagnostic and prognostic biomarkers in multiple myeloma

4.8 Therapeutic potential of noncoding RNAs in multiple myeloma patients

4.9 Summary and conclusion

Acknowledgments

References

Chapter 5. Clinical applications of noncoding RNAs in lung cancer patients

Abstract

Abbreviations

5.1 Introduction

5.2 Experimental methods and tools for analyzing ncRNAs in lung cancer patients

5.3 Datasets and informatics for analyzing ncRNAs in lung cancer patients

5.4 Expression of ncRNAs in lung cancer patients

5.5 Sample types used for analyzing ncRNAs

5.6 Cell signaling pathways modulated by ncRNAs in lung cancer patients

5.7 NcRNAs as predictive markers for lung cancer patients

5.8 Diagnostic potential of ncRNAs in lung cancer patients

5.9 Prognostic potential of ncRNAs in lung cancer patients

5.10 Therapeutic potential of ncRNAs in lung cancer patients

5.11 Potential of ncRNAs in predicting chemoresistance and radioresistance in lung cancer patients

5.12 Summary and conclusion

Acknowledgments

References

Chapter 6. Noncoding RNAs in intraocular tumor patients

Abstract

6.1 Introduction

6.2 Retinoblastoma

6.3 Uveal melanoma

6.4 Conclusion

References

Chapter 7. Applications of noncoding RNAs in renal cancer patients

Abstract

7.1 Introduction

7.2 Datasets and informatics for analyzing noncoding RNAs in renal cancer patients

7.3 Expression of noncoding RNAs in renal cancer patients

7.4 Cell signaling pathways modulated by noncoding RNAs in renal cancer patients

7.5 Diagnostic potential of noncoding RNAs in renal cancer patients

7.6 Prognostic potential of noncoding RNAs in renal cancer patients

7.7 Therapeutic potential of noncoding RNAs in renal cancer patients

7.8 Potential of noncoding RNAs in predicting chemoresistance and radioresistance in renal cancer patients

7.9 Summary and conclusion

References

Chapter 8. Clinical significance of long noncoding RNAs in breast cancer patients

Abstract

Abbreviations

8.1 Introduction

8.2 Potential of lncRNAs in the diagnosis of breast cancer

8.3 Potential of lncRNAs in the prognosis of breast cancer

8.4 Potential of lncRNAs in breast cancer therapy

8.5 Potential of lncRNAs in predicting breast cancer patient’s response to therapeutics

8.6 Potential of lncRNAs in predicting chemoresistance and radioresistance in breast cancer patients

8.7 Experimental methods and tools for analyzing noncoding RNAs in cancer patients

8.8 Summary and conclusion

Acknowledgment

References

Chapter 9. Noncoding ribonucleic acids in gastric cancer patients

Abstract

9.1 Introduction

9.2 Experimental methods and tools for analyzing noncoding RNAs in gastric cancer patients

9.3 Expression of noncoding RNAs in gastric cancer patients

9.4 Sample types used for analyzing noncoding RNAs (tumor biopsies, liquid biopsies, etc.)

9.5 Cell signaling pathways modulated by noncoding RNAs in gastric cancer patients

9.6 Noncoding RNAs as prognostic and predictive marker for gastric cancer patients

9.7 Diagnostic value of small noncoding RNAs in gastric cancer

9.8 Potential of noncoding RNAs in predicting chemotherapy resistance and radiotherapy resistance in gastric cancer patients

9.9 Summary and conclusion

References

Chapter 10. Noncoding RNAs in prostate cancer patients

Abstract

10.1 Introduction

10.2 Experimental methods and tools for analyzing ncRNAs in prostate cancer patients

10.3 Datasets and informatics for analyzing noncoding RNAs

10.4 Sample types used for analyzing ncRNAs (tumor biopsies, liquid biopsies, etc.)

10.5 Cell signaling pathways modulated by ncRNAs in prostate cancer

10.6 NcRNAs as biomarkers for prostate cancer

10.7 Therapeutic potential of ncRNAs in prostate cancer patients

10.8 Potential of ncRNAs in predicting chemo-resistance and radioresistance in prostate cancer patients

10.9 Conclusion

References

Chapter 11. Noncoding RNAs in liver cancer patients

Abstract

Abbreviations

11.1 Introduction

11.2 NcRNA roles in liver development and functions

11.3 Noncoding RNA detection

11.4 Expression of ncRNAs in liver cancers

11.5 Noncoding RNA relevance in liver cancer diagnosis and prognosis

11.6 Summary and conclusion

Acknowledgments

References

Chapter 12. Noncoding ribonucleic acids in gallbladder cancer patients

Abstract

12.1 Introduction

12.2 MiRNAs in gallbladder carcinoma

12.3 LncRNAs in gallbladder carcinoma

12.4 PiRNAs in gallbladder carcinoma

12.5 Limitations of clinical utility of ncRNAs in gallbladder carcinoma

12.6 Conclusion

References

Chapter 13. Clinical implications of noncoding RNAs in neuroblastoma patients

Abstract

13.1 Introduction

13.2 Types of noncoding RNAs

13.3 Role of noncoding RNAs in neuroblastoma growth and development

13.4 Clinical significance of noncoding RNAs in neuroblastoma

13.5 Therapeutic implications and targeting strategies for noncoding RNAs in neuroblastoma

13.6 Conclusion

Acknowledgments

Conflict of interest

References

Chapter 14. Potential clinical application of lncRNAs in pediatric cancer

Abstract

14.1 Introduction

14.2 Experimental and bioinformatics tools for studying lncRNAs

14.3 LncRNAs in pediatric cancer

14.4 Conclusion and perspectives

Acknowledgment

References

Index

Copyright

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List of contributors

Atiyeh Al-e-Ahmad

Student Research Committee, Babol University of Medical Sciences, Babol, Iran

Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran

Najeeb Al-Hallak,     Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Bayan Al-Share,     Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Nikee Awasthee,     Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

Asfar S. Azmi,     Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Manuel F. Bande

Department of Ophthalmology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Pranjal K. Baruah,     Department of Applied Sciences, GUIST, Gauhati University, Guwahati, India

Tushar Singh Barwal,     Department of Zoology, Central University of Punjab, Bathinda, India

Sonali Bazala,     Department of Zoology, Central University of Punjab, Bathinda, India

María José Blanco-Teijeiro

Department of Ophthalmology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Kishore B. Challagundla

Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States

The Children’s Health Research Institute, University of Nebraska Medical Center, Omaha, NE, United States

Ravindresh Chhabra,     Department of Biochemistry, Central University of Punjab, Bathinda, India

Antoine David,     INSERM U976, Saint-Louis Institute for Research, University of Paris, Paris, France

Lusine Demirkhanyan,     Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL, United States

Manal S. Fawzy

Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia

Daniel Fernandez-Diaz

Department of Ophthalmology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Beatriz Fernandez-Marta,     Department of Ophthalmology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

David Garrick,     INSERM U976, Saint-Louis Institute for Research, University of Paris, Paris, France

Christopher S. Gondi

Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL, United States

Department of Surgery, University of Illinois College of Medicine Peoria, Peoria, IL, United States

Department of Health Science Education and Pathology, University of Illinois College of Medicine Peoria, Peoria, IL, United States

Michele Goodhardt,     INSERM U976, Saint-Louis Institute for Research, University of Paris, Paris, France

Angélique Gougelet,     Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team Oncogenic Functions of Beta-Catenin Signaling in the Liver, Paris, France

Bela Goyal,     Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India

Małgorzata Grabowska,     Department of Molecular Neurooncology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland

Amit Gupta,     Department of General Surgery, All India Institute of Medical Sciences, Rishikesh, India

Subash C. Gupta

Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India

Sweety Gupta,     Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, India

Tarunima Gupta,     Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India

Muhib Haidari,     Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States

Aklank Jain,     Department of Zoology, Central University of Punjab, Bathinda, India

Mohammad Amin Kerachian,     Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Ajay Kumar,     Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India

Santosh Kumar,     Department of Life Science, National Institute of Technology, Rourkela, India

Nerea Lago-Baameiro,     Obesidomics Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Julia O. Misiorek,     Department of Molecular Neurooncology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland

Emadoddin Moudi,     Department of Urology, Babol University of Medical Sciences, Babol, Iran

Masang Murmu,     Department of Zoology, Central University of Punjab, Bathinda, India

Nahid Neamati

Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran

Priyasha Neyol,     Department of Biochemistry, Central University of Punjab, Bathinda, India

Laura Paniagua,     Department of Ophthalmology, University Hospital of Coruña, La Coruña, Spain

María Pardo

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Obesidomics Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Hadi Parsian

Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran

Anup S. Pathania,     Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States

Antonio Piñeiro

Department of Ophthalmology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Philip Prathipati,     Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan

Vipin Rai,     Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

Katarzyna Rolle,     Department of Molecular Neurooncology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland

Julie Sanceau,     Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team Oncogenic Functions of Beta-Catenin Signaling in the Liver, Paris, France

Jessica A. Sedhom,     Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States

Rachel Sexton,     Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Anurag Sharma,     Division of Environmental Health and Toxicology, Nitte (Deemed to Be University), Nitte University Centre for Science Education and Research (NUCSER), Mangalore, India

Uttam Sharma,     Department of Zoology, Central University of Punjab, Bathinda, India

Anusmita Shekher,     Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

Paula Silva-Rodríguez

Intraocular Tumors in Adults, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Galician Public Foundation of Genomic Medicine, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Ipsa Singh,     Department of Zoology, Central University of Punjab, Bathinda, India

Oghenetejiri V. Smith,     Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States

Anteneh Tesfaye,     Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Eman A. Toraih

Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States

Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Naveen Kumar Vishvakarma,     Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India

Simin Younesi,     School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia

Żaneta Zarębska,     Department of Molecular Neurooncology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland

Simone Zocchi,     INSERM U976, Saint-Louis Institute for Research, University of Paris, Paris, France

Preface

Subash Chandra Gupta and Kishore B. Challagundla

Despite significant advances in understanding the pathogenesis, cancer continues to be the second leading cause of death worldwide. This is partly due to delayed diagnosis, poor prognosis, recurrence, and resistance mechanisms by cancer cells. Almost 98% of the human genome consists of noncoding sequences. However, most of the currently available cancer biomarkers and therapeutic targets are based on coding genes. Of the noncoding sequences, up to 90% are transcribed, producing a vast number of noncoding RNAs (ncRNAs). Two major types of ncRNAs are microRNAs (miRNAs) (18–22 nucleotides) and long noncoding RNAs (lncRNAs, ≥200 nucleotides). Although much is known about miRNAs, very little is known about lncRNAs. This is evident from the PubMed database where keywords microRNA+cancer produced 59,353 articles on July 6, 2021. However, a steep rise in the field of lncRNAs has been witnessed in the recent past. The advent of sensitive, high-throughput genomic technologies such as microarrays and next-generation sequencing has enabled to detection of novel transcripts, the vast majority of which are derived from noncoding sequences of human genome. As of July 6, 2021, more than 17,900 entries were listed in the PubMed database with the keywords long noncoding RNA+cancer. Some lncRNAs function as tumor suppressors, some as an oncogene, some as both oncogene and tumor suppressors, while the functions of several others remain unknown. Recent studies suggest that miRNAs and lncRNAs can be used as a biomarker. The ncRNAs also offer the potential to be a novel class of therapeutic cancer targets. The strategies could be either to suppress oncogenic function or to activate the tumor-suppressive activity of specific ncRNAs.

This book is an effort to provide in-depth information on the potential of ncRNAs in cancer diagnosis, prognosis, and therapy. The focus is on two major types of ncRNAs, that is, miRNAs and lncRNAs. The chapters cover the clinical applications of ncRNAs in diverse cancer types such as pancreatic, brain, colorectal, lung, bladder, renal, breast, gastric, prostate, liver, gallbladder, pediatric, and in patients with multiple myeloma, intraocular tumor, and neuroblastoma. The experimental methods and tools for analyzing ncRNAs in these cancer types are covered. In addition, the experts have discussed several other emerging topics with reference to the clinical utility of ncRNAs, such as datasets and informatics for analysis, sample types being used, cell signaling pathways being modulated, and potential of ncRNAs in predicting chemoresistance and radioresistance.

We hope that the book will be useful to the readers. We thank the authors for their outstanding contribution to this book and apologize to those whose contributions could not be solicited due to space limitations.

Chapter 1

Noncoding ribonucleic acid for pancreatic cancer therapy

Lusine Demirkhanyan¹ and Christopher S. Gondi¹, ², ³,    ¹Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL, United States,    ²Department of Surgery, University of Illinois College of Medicine Peoria, Peoria, IL, United States,    ³Department of Health Science Education and Pathology, University of Illinois College of Medicine Peoria, Peoria, IL, United States

Abstract

Major hallmarks of pancreatic ductal adenocarcinomas (PDACs) include tumor recurrence and extremely poor response to chemotherapy and are able to form metastatic tumors indistinguishable from the parental tumors and contribute to chemo resistance. Pancreatic cancer (PC) is extensive local tumor invasion, early systemic dissemination, and extremely poor response to chemotherapy. The status of PDAC therapy is still poor and a lot more needs to be done to improve therapeutic outcomes. Numerous gene expression products have been correlated with these hallmarks, including noncoding RNA (ncRNA). All gene expression are in some way modulated by ncRNAs, and the involvement of numerous gene mutations in the ncRNA network can also add to the complexity of PC molecular profile. In this review, we will discuss about the current status of methods and tools for analyzing ncRNAs, and the PDAC-specific ncRNA. We will also touch upon the diagnostic and therapeutic potential of ncRNA in PDACs.

Keywords

Pancreatic ductal adenocarcinoma (PDAC); noncoding RNA (ncRNA); microRNA (miRNA); long noncoding RNA (lncRNA); circular RNA (circRNA); endoscopic ultrasound (EUS); fine needle aspiration (FNA) biopsy; next-generation sequencing (NGS); KRAS; miR21; miR155; miR196s; 196b; miR217; SNHG16; SOX2OT; GAS5; hsa_circ_001653; ciRS-7; circNFIB1

1.1 Introduction

Various types of noncoding RNAs (ncRNA) have been identified and the classification of these RNAs continues to evolve with steady progress. Historically RNAs are considered templates for protein synthesis, and RNAs that did not code for protein synthesis were considered by-products of transcription. The synergism of large-scale sequence with powerful computing tools has helped unravel the cryptic role of RNAs. This large-scale genome analysis revealed that most of the so-called junk DNA is transcribed to what is now called ncRNA (Eddy, 2001). It is now known that ncRNAs are found in almost all biological processes, including pathologies such as cancer (Pavet, Portal, Moulin, Herbrecht, & Gronemeyer, 2011). In this review, we will focus on the roles of some of these ncRNAs involved in pancreatic cancers (PCs) and the potential these ncRNAs can have in PC therapy. Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer deaths in the United States and accounts for over 95% of all PCs. The combined 1- and 5-year survival rates for PDAC are very poor, at 25% and 9%, respectively. A major hallmark of PC is tumor recurrence and extremely poor response to chemotherapy and is able to form metastatic tumors indistinguishable from the parental tumors and contribute to chemo resistance (Clarke, Fuller, 2006; Dean, Fojo, & Bates, 2005; Dingli, Michor, 2006; Reya, Morrison, Clarke, & Weissman, 2001; Hermann, Huber et al., 2007; Ailles, Weissman, 2007; Moltzahn, Volkmer, Rottke, & Ackermann, 2008; Moriyama, Ohuchida et al., 2010; Subramaniam, Ramalingam, Houchen, & Anant, 2010; Asuthkar, Stepanova et al., 2013; Du, Qin et al., 2010; Du, Qin et al., 2011; Hamada, Shimosegawa, 2012; Ischenko, Seeliger et al., 2010; Rossi, Rehman, & Gondi, 2014; Schober, Jesenofsky et al., 2014; Wang et al., 2011; Wei, Yin et al., 2011). PDAC tumors often reoccur after surgery and chemotherapy. These new tumors tend to be chemoresistant, which leads to poor survival and the survival rates have not increased in the last 50 years (American Cancer Society, 2013). PC is extensive local tumor invasion, early systemic dissemination, and extremely poor response to chemotherapy (Buell-Gutbrod, Cavallo, Lee, Montag, & Gwin, 2015; Harvey et al., 2003; Hasegawa et al., 2014; Hu, Scott et al., 2013; Iacopino, Angelucci et al., 2014; Ilmer, Boiles et al., 2015; Pandian, Ramraj, Khan, Azim, & Aravindan, 2015; Pearton, Smith et al., 2014; Shekhani, Jayanthy, Maddodi, & Setaluri, 2013; Gibbs, Schlieman et al., 2009; Watabe, Yoshida et al., 1998). The current status of PDAC therapy is still poor and a lot more needs to be done to improve therapeutic outcomes (Froeling, Casolino, Pea, Biankin, & Chang, 2021; Parrasia, Zoratti, Szabò, & Biasutto, 2021; Santofimia-Castaño, Iovanna, 2021; Sun, Russell, Scarlett, & McCluskey, 2020; Wu et al., 2021). Most PCs are associated with mutations in Kirsten rat sarcoma virus (KRAS), TP53, SMAD4, CDKN2A genes and associated pathways such as Wnt/Notch, Hippo, Hedgehog, and the Pi3k-Akt pathways (Waddell et al., 2015); recently a genome-wide metaanalysis has identifies new susceptibility loci for PC indicating that there may be multiple subtypes of PCs. All gene expressions are in some way controlled or modulated by ncRNAs and the involvement of numerous gene mutations in the ncRNA network can also add to the complexity of PC molecular profile (Obazee et al., 2018; Walsh et al., 2019; Zhang et al., 2016).

1.2 Experimental methods and tools for analyzing noncoding RNAs in pancreatic cancer patients

Considering the importance of early detection and diagnosis of PC at a stage potentially curable, still limited number of experimental methods and approaches are available. Imaging techniques and biomarkers are two major methods widely used for this purpose. Among imaging methods, the most efficient one is an endoscopic ultrasound (EUS) (Gheorghe, Bungau et al., 2020; Iordache, Albulescu, & Săftoiu, 2017) with high sensitivity and specificity to PC detection. It allows detecting deeply localized tumors, as well as obtaining a biological sample by fine needle aspiration (FNA) biopsy following histological and molecular examination. In complement to this, recent development of molecular diagnosis field brought up some new epigenetic biomarkers, circulating tumor deoxyribonucleic acids, microRNAs (miRNAs), and other ncRNAs with high potential for early PC detection. There is growing interest to regulatory ncRNAs, such as miRNAs, long noncoding RNA (lncRNAs), and circular RNAs (circRNAs), that are involved in many cellular processes, including tumorigenesis (Gheorghe, Bungau et al., 2020; Słotwiński, Lech, & Słotwińska, 2018; Vila-Navarro et al., 2017; Vila-Navarro, Duran-Sanchon et al., 2019). Evidences of dysregulation of these RNAs in PC tissue samples and pancreatic precursor lesions obtained by EUS–FNA or after a surgical biopsy, in plasma, saliva, stool samples of patients are accumulating at express speed. Most of the studies are based on messenger RNA (mRNA)/miRNA sequencing, lncRNA, circRNA, or Piwi-interacting RNA (piRNA) microarrays, following excessive bioinformatic analysis. Using genome-wide miRNA profiling by next-generation sequencing (NGS), Vila-Navarro et al. (2017) were able to identify 607 deregulated miRNAs in PDAC and 396 miRNAs in intraductal papillary mucinous neoplasm (IPMN), compared with healthy individuals. Total 30 overexpressed miRNAs were validated by quantitative reverse transcriptase polymerase chain reaction. The circRNA and miRNA microarray data from other group of investigators reveal differentially expressed 256 circRNAs and 20 miRNAs from PDAC tissues compared to normal. Using Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that 41 circRNAs out of 256 were enriched in 17 pathways (Zhang, Wang, Zhou, Yang, & Zhong, 2019). Raulefs et al. demonstrated altered miRNA regulation of coding gene expression in PDAC compared to normal pancreatic tissues using high-throughput NGS-based technologies, namely, Massive Analysis of complementary DNA Ends and small RNA sequencing. Differential expressed other ncRNAs (piRNA, several seed region RNA, long intergenic noncoding RNAs [lincRNAs], and natural antisense transcripts) were studied in PDAC, too (Muller et al., 2015). Although relevance and validity of ncRNA as diagnostics is well known, no ncRNAs are currently in the clinical diagnostic phase (Sharma, Okada, Von Hoff, & Goel, 2020).

1.3 Bioinformatics for analyzing noncoding RNAs in pancreatic cancer patients

Numerous approaches have been developed to characterize ncRNA expression profiles from published sequencing data. Recently researchers were able to demonstrate the use of a resource allocation technique in ncRNA–target–disease tripartite network and correlate with disease prediction (Mori, Ngouv, Hayashida, Akutsu, & Nacher, 2018). In another study specific to PDAC, researches used miRNA–mRNA interactions followed by high-throughput sequencing (CLIP-Seq) data from StarBas, identified differentially expressed 500 miRNAs, and 21 lncRNAs, and were further able to predict a dual transcription factor–miRNA–mRNA, lncRNA–miRNA–mRNA regulatory mechanisms in PC (Ye, Yang et al., 2014). Researchers have also used multiomics data (Mishra, Southekal et al., 2019), penalized algorithms (Lee, Lee et al., 2021), and integrating transcriptome analysis (Yang & Zeng, 2015) for identifying novel PDAC-specific ncRNA markers from available databases. It is worth mentioning that with the development of deep learning machine algorithms, the identification of novel and clinically relevant ncRNAs will increase significantly (Shaw, Chen, Xie, & Jiang, 2021; Yang et al., 2020; Zhang, Long, & Kwoh, 2020).

1.4 Noncoding RNA

Noncoding RNAs (ncRNAs) can be classified into two types, regular and regulatory (Fig. 1.1). Regular ncRNA consists of RNA molecules involved in the normal biological functioning of cells such as ribosomal RNA, transfer RNA (tRNA), small nuclear RNA, small nucleolar RNAs, telomerase RNA component, transfer RNA-derived RNA fragments, and tRNA-derived stress-induced RNAs, and regulatory ncRNAs consist of molecules such as miRNA (Ambros, 2001; Toscano-Garibay, Aquino-Jarquin, 2014), small interfering RNA (siRNA) (Chen et al., 2018; Shi, Jin, Song, & Chen, 2019), piRNA (Muller et al., 2015; Saito, Sakaguchi et al., 2007), enhancer RNA (Amirnasr, Sleijfer, & Wiemer, 2020; Parrasia, Zoratti et al., 2021; Shimamura, Nakagami, Sanada, & Morishita, 2020), lncRNA (Ding, Li et al., 2020; Guo et al., 2020), circRNA (Arnaiz, Sole et al., 2018; Shang, Yang, Jia, & Ge, 2019; Wang et al., 2019), and small noncoding RNA (Zhang, Wu, Chen, & Chen, 2019). More and more types of ncRNAS continue to be identified on a regular basis, for example, tsRNAs (Zong et al., 2021). Significant amount of progress has been made in the identification and characterization of siRNA, miRNA, circRNA, and lncRNA in relation to PDAC; however, more amount of research is required for other types of ncRNA. We will focus on miRNA, circRNA, and lncRNA.

Figure 1.1 Classification of noncoding RNA based on function.

1.5 Pancreatic cancer–specific microRNAs

miRNAs regulate most biological processes. More than a decade ago, it was shown that miRNAs were small RNA molecules of about 22 nucleotides (~22 nt) in length that probably function as antisense regulators of other RNAs (Ambros, 2001). The mechanisms of miRNA action are now much clearer though not complete (Toscano-Garibay, Aquino-Jarquin, 2014). Their capacity of regulating mRNAs and even other miRNAs is being reported with increasing frequency, making it a powerful tool for gene regulation. In more than 90% of PDACs show activating mutations of KRAS (Almoguera, Shibata et al., 1988). KRAS targeting miRs such as miRNA-96, 126, and 217 were observed to be downregulated in most PDACs. Diab, Muqbil, Mohammad, Azmi, and Philip (2016) recently published a detailed review of up- and downregulated miRs associated with PDAC. miR21, miR155, miR196s, and 196b are considered to be the most reliable preclinical PDAC markers (Wang et al., 2009) (Table 1.1).

Table 1.1

miRNA, MicroRNA; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma.

1.6 Pancreatic cancer–associated lncRNAs

lncRNAs have multifunctional roles such as signaling regulation and cancer metastasis (Ming, Li et al., 2021). However, only a few lincRNAs have been identified that show specific association with PDACs (Table 1.2). SNHG16 and SOX2OT are known to be upregulated in PC tissues and function by sponging away miR-200a-3p and miR-200a/141 ( Guo et al., 2020). GAS5 on the other hand is shown to be downregulated in PC cells and targets miR-221/SOCS3 that are known contributors of chemoresistance and metastasis (Liu, Wu et al., 2018) (Table 1.2).

Table 1.2

PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma.

1.7 Pancreatic cancer–associated circular RNAs

One of the roles of this new class of RNAs is to function as sponges that tightly regulate the availability of miRNAs (Yang, Fu, & Zhou, 2018). Further, another regulatory layer is being classified at the RNA level, which includes various ncRNAs (Garajova, Balsano, Tommasi, & Giovannetti, 2019; Wong, Sorensen, Joglekar, Hardikar, & Dalgaard, 2018; Zang, Lu, & Xu, 2018). circRNAs that were thought to belong to this group of ncRNAs are now slowly being recognized as belonging to a significantly importantly regulatory layer which can also code for proteins (Arnaiz, Sole et al., 2018; Shang, Yang et al., 2019; Wang et al., 2019). It is now recognized that most protein-coding genes not only produce linear mRNA but also produce circRNAs and this output ratio from linear to circular is dependent on the efficiency of pre-mRNA processing (Liang, Tatomer et al., 2017; Qu, Zhong et al., 2016) (Table 1.3).

Table 1.3

KRAS, Kirsten rat sarcoma virus; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma.

1.8 Diagnostic microRNA markers of PDAC

Lately, liquid biopsy based on miRNAs continues to attract interest as early diagnostics of PCs. It has been demonstrated that miRNAs are highly conserved and are stable in biological fluids (Lagos-Quintana, Rauhut et al., 2001) making them attractive biomarkers for various pathologies. Numerous upregulated micro-RNAs have been identified in PDAC patients when compared to controls [for detailed list please see references (Diab, Muqbil et al., 2016; Wang et al., 2009)]. Among all the miRs up- or downregulated in PDACs, miR217 stands out (Hernandez, Lucas, 2016; Hong, Park, 2014; Vychytilova-Faltejskova et al., 2015; Yang, Zhang, & Qin, 2017). In PDACs, it is known that miR217 is downregulated. MiR217 is known to target KRAS that is significant in PDACs. It was recently shown that miR217 is a diagnostic biomarker and is involved in human podocyte cells apoptosis via targeting TNFSF11 (Li, Liu et al., 2017) and was shown to regulate the Rat sarcoma virus-mitogen-activated protein kinases signaling pathway in colorectal cancer (Zhang, Lu, & Chen, 2016) (Table 1.1).

1.9 Diagnostic lncRNA markers of PDAC

Numerous lncRNAs have been identified both experimentally and by computational analysis. A recent study has identified key lncRNAs involved in the progression of intraductal IPMN to PDAC (Ding, Li et al., 2020). These newer findings have not yet been translated to a clinical setting (Table 1.2).

1.10 Diagnostic circular RNA markers of PDAC

After miRNAs, circRNAs are the most studied ncRNAs. circRNAs are circular in shape and lack a 5′ cap or 3′ poly-A tail and are more stable than linear mRNAs to traditional RNA degradation (Chen & Yang, 2015). Numerous studies have documented the expressions of circRNAs in PDAC using techniques such as microarray analysis and computational analysis from both cell lines and tissue samples (Table 1.3). However, no circRNA is currently being used to actively validate clinical outcome. It was recently shown that hsa_circ_001653 is significantly involved in the development of PDAC (Shi et al., 2020). It is known that hsa_circ_001653 targets miR217, which targets E2F3, PRSS3, KRAS, and SIRT1 (Table 1.3). As stated earlier in more than 90% of PDACs show activating mutations of KRAS (Almoguera, Shibata et al., 1988), therefore suggesting that hsa_circ_001653 expression activates KRAS expression and can be a significant diagnostic marker for PDAC.

1.11 Summary and conclusion

Recent studies have shown that lncRNA HOST2 (An, Cheng, 2020), has-miR125a (Yong, Yabin et al., 2017), and miR21 (Diab, Muqbil et al., 2016; Giovannetti et al., 2010; Sun et al., 2019; Wang et al., 2009; Zhao, Chen et al., 2018) correlate with Gemcitabine resistance and miR-320a modulates 5-FU response (Yong, Yabin et al., 2017). In another study, researchers found a core miRNA–mRNA regulatory network involving hsa-miR-643, hsa-miR-4644, hsa-miR-4650–5p, hsa-miR-4455, hsa-miR-1261, and hsa-miR-3676 as predictors of gemcitabine-resistant (Shen, Pan et al., 2015).

Acknowledgment

Support for this study by the McElroy Foundation and the Theresa Tracy Trott Foundation is acknowledged.

References

Ailles and Weissman, 2007 Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Current Opinion in Biotechnology. 2007;5:460–466.

Almoguera et al., 1988 Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;4:549–554.

Ambros, 2001 Ambros V. microRNAs: Tiny regulators with great potential. Cell. 2001;7:823–826.

American Cancer Society, 2013 American Cancer Society. Cancer facts & figures Atlanta, GA: American Cancer Society; 2013.

Amirnasr et al., 2020 Amirnasr A, Sleijfer S, Wiemer EAC. Non-coding RNAs, a novel paradigm for the management of gastrointestinal stromal tumors. International Journal of Molecular Sciences. 2020;18:E6975 https://doi.org/10.3390/ijms21186975.

An and Cheng, 2020 An N, Cheng D. The long noncoding RNA HOST2 promotes gemcitabine resistance in human pancreatic cancer cells. Pathology & Oncology Research. 2020;1:425–431.

An and Zheng, 2020 An N, Zheng B. MiR-203a-3p inhibits pancreatic cancer cell proliferation, EMT, and apoptosis by regulating SLUG. Technology in Cancer Research & Treatment. 2020;19 1533033819898729.

Arnaiz et al., 2018 Arnaiz E, Sole C, Manterola L, Iparraguirre L, Otaegui D, Lawrie CH. CircRNAs and cancer: Biomarkers and master regulators. Seminars in Cancer Biology. 2018;58.

Asuthkar et al., 2013 Asuthkar S, Stepanova V, Lebedeva T, et al…. Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer. Molecular Biology of the Cell. 2013;17:2620–2632.

Buell-Gutbrod et al., 2015 Buell-Gutbrod R, Cavallo A, Lee N, Montag A, Gwin K. Heart and neural crest derivatives expressed transcript 2 (HAND2): A novel biomarker for the identification of atypical hyperplasia and type I endometrial carcinoma. International Journal of Gynecological Pathology. 2015;1:65–73.

Calatayud et al., 2017 Calatayud D, Dehlendorff C, Boisen MK, et al…. Tissue microRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers. Biomarker Research. 2017;5 8–017-0087-6. eCollection 2017.

Chang et al., 2017 Chang X, Yu C, Li J, Yu S, Chen J. hsa-miR-96 and hsa-miR-217 expression down-regulates with increasing dysplasia in pancreatic intraepithelial neoplasias and intraductal papillary mucinous neoplasms. International Journal of Medical Sciences. 2017;5:412–418.

Chaudhary et al., 2017 Chaudhary AK, Mondal G, Kumar V, Kattel K, Mahato RI. Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205. Cancer Letters. 2017;402:1–8.

Chen et al., 2017 Chen G, Shi Y, Zhang Y, Sun J. CircRNA_100782 regulates pancreatic carcinoma proliferation through the IL6-STAT3 pathway. OncoTargets and Therapy. 2017;10:5783–5794.

Chen and Yang, 2015 Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biology. 2015;4:381–388.

Chen et al., 2018 Chen X, Mangala LS, Rodriguez-Aguayo C, Kong X, Lopez-Berestein G, Sood AK. RNA interference-based therapy and its delivery systems. Cancer and Metastasis Reviews. 2018;1:107–124.

Chen et al., 2019 Chen Y, et al. Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma. Journal of Experimental & Clinical Cancer Research. 2019;1:466–019-1436-0.

Choi et al., 2014 Choi CI, Lee SH, Hwang SH, et al…. Single-incision intragastric resection for upper and mid gastric submucosal tumors: A case-series study. Annals of Surgical Treatment and Research. 2014;6:304–310.

Clarke and Fuller, 2006 Clarke MF, Fuller M. Stem cells and cancer: Two faces of eve. Cell. 2006;6:1111–1115.

Cui et al., 2019 Cui K, Jin S, Du Y, et al. Long noncoding RNA DIO3OS interacts with miR-122 to promote proliferation and invasion of pancreatic cancer cells through upregulating ALDOA. Cancer Cell International. 2019;19 202-019-0922-y. eCollection 2019.

Dai et al., 2020 Dai C, Zhang Y, Xu Z, Jin M. MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma. Cancer Cell International. 2020;20 98-020-01185-z. eCollection 2020.

Dean et al., 2005 Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nature Reviews Cancer. 2005;4:275–284.

Diab et al., 2016 Diab M, Muqbil I, Mohammad RM, Azmi AS, Philip PA. The role of microRNAs in the diagnosis and treatment of pancreatic adenocarcinoma. Journal of Clinical Medicine. 2016;6:59 https://doi.org/10.3390/jcm5060059.

Ding et al., 2020 Ding J, Li Y, Zhang Y, et al. Identification of key lncRNAs in the tumorigenesis of intraductal pancreatic mucinous neoplasm by coexpression network analysis. Cancer Medicine. 2020;11:3840–3851.

Dingli and Michor, 2006 Dingli D, Michor F. Successful therapy must eradicate cancer stem cells. Stem Cells. 2006;12:2603–2610.

Du et al., 2011 Du Z, Qin R, Wei C, et al. Pancreatic cancer cells resistant to chemoradiotherapy rich in stem-cell-like tumor cells. Digestive Diseases and Sciences. 2011;3:741–750.

Du et al., 2010 Du Z, Qin R, Wei C, et al. Pancreatic cancer cells resistant to chemoradiotherapy rich in Stem-Cell-Like tumor cells. Digestive Diseases and Sciences. 2010;56.

Eddy, 2001 Eddy SR. Non-coding RNA genes and the modern RNA world. Nature Reviews Genetics. 2001;12:919–929.

Froeling et al., 2021 Froeling FEM, Casolino R, Pea A, Biankin AV, Chang DK. Molecular subtyping and precision medicine for pancreatic cancer. Journal of Clinical Medicine. 2021;1:149 https://doi.org/10.3390/jcm10010149.

Gao et al., 2019 Gao Y, Zhang Z, Li K, et al…. Author correction: Linc-DYNC2H1–4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells. Cell Death & Disease. 2019;8:604–019-1852-2.

Garajova et al., 2019 Garajova I, Balsano R, Tommasi C, Giovannetti E. Noncoding RNAs emerging as novel biomarkers in pancreatic cancer. Current Pharmaceutical Design. 2019;24.

Gheorghe et al., 2020 Gheorghe G, Bungau S, Ilie M, et al…. Early diagnosis of pancreatic cancer: The key for survival. Diagnostics (Basel). 2020;11:869 https://doi.org/10.3390/diagnostics10110869.

Gibbs et al., 2009 Gibbs JF, Schlieman M, Singh P, et al. A pilot study of urokinase-type plasminogen activator (uPA) overexpression in the brush cytology of patients with malignant pancreatic or biliary strictures. HPB Surgery. 2009;2009 Article ID 805971.

Giovannetti et al., 2010 Giovannetti E, et al. MicroRNA-21 in pancreatic cancer: Correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Research. 2010;11:4528–4538.

Guo et al., 2020 Guo JQ, Yang ZJ, Wang S, Wu ZZ, Yin LL, Wang DC. LncRNA SNHG16 functions as an oncogene by sponging miR-200a-3p in pancreatic cancer. European Review for Medical and Pharmacological Sciences. 2020;4:1718–1724.

Guo et al., 2020 Guo W, Zhao L, Wei G, Liu P, Zhang Y, Fu L. Blocking circ_0013912 suppressed cell growth, migration and invasion of pancreatic ductal adenocarcinoma cells in vitro and in vivo partially through sponging miR-7-5p. Cancer Management and Research. 2020;12:7291–7303.

Guo et al., 2020 Guo X, et al. Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis. Molecular Cancer. 2020;1 83-020-01196-4.

Guo et al., 2020 Guo Z, Wang X, Yang Y, et al…. Hypoxic tumor-derived exosomal long noncoding RNA UCA1 promotes angiogenesis via miR-96-5p/AMOTL2 in pancreatic cancer. Molecular Therapy – Nucleic Acids. 2020;22:179–195.

Hamada and Shimosegawa, 2012 Hamada S, Shimosegawa T. Pancreatic cancer stem cell and mesenchymal stem cell. In: Grippo PJ, Munshi HG, eds. Pancreatic cancer and tumor microenvironment. Trivandrum: Transworld Research Network; 2012.

Hao et al., 2019 Hao L, Rong W, Bai L, et al…. Upregulated circular RNA circ_0007534 indicates an unfavorable prognosis in pancreatic ductal adenocarcinoma and regulates cell proliferation, apoptosis, and invasion by sponging miR-625 and miR-892b. Journal of Cellular Biochemistry. 2019;3:3780–3789.

Harvey et al., 2003 Harvey SR, et al. Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer. Clinical Cancer Research. 2003;13:4935–4943.

Hasegawa et al., 2014 Hasegawa S, et al. MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer. British Journal of Cancer. 2014;8:1572–1580.

Hermann et al., 2007 Hermann PC, Huber SL, Herrler T, et al…. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;3:313–323.

Hernandez and Lucas, 2016 Hernandez YG, Lucas AL. MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions. World Journal of Gastrointestinal Oncology. 2016;1:18–29.

Hong and Park, 2014 Hong TH, Park IY. MicroRNA expression profiling of diagnostic needle aspirates from surgical pancreatic cancer specimens. Annals of Surgical Treatment and Research. 2014;6:290–297.

Hu et al., 2013 Hu D, Scott IC, Snider F, et al. The basic helix-loop-helix transcription factor Hand1 regulates mouse development as a homodimer. Developmental Biology. 2013;2:470–481.

Iacopino et al., 2014 Iacopino F, Angelucci C, Piacentini R, et al…. Isolation of cancer stem cells from three human glioblastoma cell lines: Characterization of two selected clones. PLoS One. 2014;8 e105166.

Ilmer et al., 2015 Ilmer M, Boiles AR, Regel I, et al…. RSPO2 enhances canonical wnt signaling to confer stemness-associated traits to susceptible pancreatic cancer cells. Cancer Research. 2015;9:1883–1896.

Iordache et al., 2017 Iordache S, Albulescu DM, Săftoiu A. The borderline resectable/locally advanced pancreatic ductal adenocarcinoma: EUS oriented. Endosc Ultrasound. 2017;6:S83–S86.

Ischenko et al., 2010 Ischenko I, Seeliger H, Kleespies A, et al. Pancreatic cancer stem cells: New understanding of tumorigenesis, clinical implications. Langenbeck’s Archives of Surgery. 2010;1:1–10.

Jiang et al., 2018 Jiang Y, Wang T, Yan L, Qu L. A novel prognostic biomarker for pancreatic ductal adenocarcinoma: hsa_circ_0001649. Gene. 2018;675:88–93 https://doi.org/10.1016/j.gene.2018.06.099.

Kong et al., 2020 Kong Y, Li Y, Luo Y, et al. circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer. Mol Cancer. 2020;19 82-020-01205-6. PMCID: PMC7197141.

Lagos-Quintana, Rauhut, Lendeckel, & Tuschl, 2001 Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–858.

Lee et al., 2021 Lee J, Lee HS, Park SB, et al. Identification of Circulating Serum miRNAs as Novel Biomarkers in Pancreatic Cancer Using a Penalized Algorithm. Int J Mol Sci. 2021;22(3):1007 https://doi.org/10.3390/ijms22031007.

Li et al., 2018 Li J, Li Z, Jiang P, et al. Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res. 2018;37 177-018-0822-3. PMCID: PMC6069563.

Li, Liu, Xue, Zhou, & Peng, 2017 Li J, Liu B, Xue H, Zhou QQ, Peng L. miR-217 is a useful diagnostic biomarker and regulates human podocyte cells apoptosis via targeting TNFSF11 in membranous nephropathy. Biomed Res Int. 2017;2017:2168767 PMCID PMC5682891.

Li et al., 2018 Li Z, Yanfang W, Li J, et al. Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer. Cancer Lett. 2018;432:237–250.

Liang et al., 2017 Liang D, Tatomer DC, Luo Z, et al. The output of protein-coding genes shifts to circular RNAs when the pre-mRNA processing machinery is limiting. Mol Cell. 2017;68(5):940–954 e3. PMCID: PMC5728686.

Limb et al., 2020 Limb C, Liu DSK, Veno MT, et al. The role of circular RNAs in pancreatic ductal adenocarcinoma and biliary-tract cancers. Cancers (Basel). 2020;12(11):3250 https://doi.org/10.3390/cancers12113250 PMCID: PMC7694172.

Liu et al., 2018 Liu B, Wu S, Ma J, et al. lncRNA GAS5 reverses EMT and tumor stem cell-mediated gemcitabine resistance and metastasis by targeting miR-221/SOCS3 in pancreatic cancer. Mol Ther Nucleic Acids. 2018;13:472–482 https://doi.org/10.1016/j.omtn.2018.09.026 Epub 2018 Oct 6. PMID: 30388621; PMCID: PMC6205337.

Liu et al., 2013 Liu C, Cheng H, Shi S, et al. MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3. Curr Mol Med. 2013;13(4):467–478.

Liu, Zhou, Zhang, & Fu, 2020 Liu CS, Zhou Q, Zhang YD, Fu Y. Long noncoding RNA SOX2OT maintains the stemness of pancreatic cancer cells by regulating DEK via interacting with miR-200a/141. Eur Rev Med Pharmacol Sci. 2020;24(5):2368–2379.

Liu et al., 2019 Liu L, Liu FB, Huang M, et al. Circular RNA ciRS-7 promotes the proliferation and metastasis of pancreatic cancer by regulating miR-7-mediated EGFR/STAT3 signaling pathway. Hepatobiliary Pancreat Dis Int. 2019;18(6):580–586.

Liu et al., 2020 Liu Y, Xia L, Dong L, et al. CircHIPK3 promotes gemcitabine (GEM) resistance in pancreatic cancer cells by sponging miR-330-5p and targets RASSF1. Cancer Manag Res. 2020;12:921–929 PMCID: PMC7023912.

Ma et al., 2020 Ma Q, Wu H, Xiao Y, Liang Z, Liu T. Upregulation of exosomal microRNA‑21 in pancreatic stellate cells promotes pancreatic cancer cell migration and enhances Ras/ERK pathway activity. Int J Oncol. 2020;56(4):1025–1033 https://doi.org/10.3892/ijo.2020.4986 Epub 2020 Feb 14. PMID: 32319558.

Mishra, Southekal, & Guda, 2019 Mishra NK, Southekal S, Guda C. Survival Analysis of Multi-Omics Data Identifies Potential Prognostic Markers of Pancreatic Ductal Adenocarcinoma. Front Genet. 2019;10:624.

Moltzahn et al., 2008 Moltzahn FR, Volkmer JP, Rottke D, Ackermann R. Cancer stem cells-lessons from Hercules to fight the Hydra. Urologic Oncology. 2008;6:581–589.

Mori et al., 2018 Mori T, Ngouv H, Hayashida M, Akutsu T, Nacher JC. ncRNA-disease association prediction based on sequence information and tripartite network. BMC Systems Biology. 2018;37:37–018-0527-4.

Moriyama et al., 2010 Moriyama T, Ohuchida K, Mizumoto K, et al. Enhanced cell migration and invasion of CD133+ pancreatic cancer cells cocultured with pancreatic stromal cells. Cancer. 2010;14:3357–3368.

Muller et al., 2015 Muller S, et al. Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Molecular Cancer. 2015;14 94-015-0358-5.

Ni et al., 2019 Ni J, Zhou S, Yuan W, Cen F, Yan Q. Mechanism of miR-210 involved in epithelial-mesenchymal transition of pancreatic cancer cells under hypoxia. Journal of Receptor and Signal Transduction. 2019;5–6:399–406.

Obazee et al., 2018 Obazee O, et al. Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms. Carcinogenesis. 2018;3:360–367.

Ohuchida et al., 2012 Ohuchida K, et al. MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. Annals of Surgical Oncology. 2012;7:2394–2402.

Pandian et al., 2015 Pandian V, Ramraj S, Khan FH, Azim T, Aravindan N. Metastatic neuroblastoma cancer stem cells exhibit flexible plasticity and adaptive stemness signaling. Stem Cell Research & Therapy. 2015;1 2–015-0002–8.

Papaconstantinou et al., 2013 Papaconstantinou IG, Manta A, Gazouli M, et al. Expression of microRNAs in patients with pancreatic cancer and its prognostic significance. Pancreas. 2013;1:67–71.

Parrasia et al., 2021 Parrasia S, Zoratti M, Szabò I, Biasutto L. Targeting pancreatic ductal adenocarcinoma (PDAC). Cellular Physiology and Biochemistry. 2021;1:61–90.

Passadouro and Faneca, 2016 Passadouro M, Faneca H. Managing pancreatic adenocarcinoma: A special focus in MicroRNA gene therapy. International Journal of Molecular Sciences. 2016;5:718 https://doi.org/10.3390/ijms17050718.

Pavet et al., 2011 Pavet V, Portal MM, Moulin JC, Herbrecht R, Gronemeyer H. Towards novel paradigms for cancer therapy. Oncogene. 2011;1:1–20.

Pearton et al., 2014 Pearton DJ, Smith CS, Redgate E, van Leeuwen J, Donnison M, Pfeffer PL. Elf5 counteracts precocious trophoblast differentiation by maintaining Sox2 and 3 and inhibiting Hand1 expression. Developmental Biology. 2014;2:344–357.

Qu et al., 2019 Qu S, Hao X, Song W, et al…. Circular RNA circRHOT1 is upregulated and promotes cell proliferation and invasion in pancreatic cancer. Epigenomics. 2019;1:53–63.

Qu et al., 2016 Qu S, Zhong Y, Shang R, et al. The emerging landscape of circular RNA in life processes. RNA Biology. 2016;14:1–8.

Reya et al., 2001 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;6859:105–111.

Rossi et al., 2014 Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World Journal of Gastroenterology. 2014;32:11142–11159.

Saito et al., 2007 Saito K, Sakaguchi Y, Suzuki T, Suzuki T, Siomi H, Siomi MC. Pimet, the Drosophila homolog of HEN1, mediates 2′-O-methylation of Piwi-interacting RNAs at their 3′ ends. Genes & Development. 2007;13:1603–1608.

Santofimia-Castaño and Iovanna, 2021 Santofimia-Castaño P, Iovanna J. Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways. Pancreatology. 2021;21.

Schlick et al., 2020 Schlick K, et al. Overcoming negative predictions of microRNA expressions to gemcitabine response with FOLFIRINOX in advanced pancreatic cancer patients. Future Science OA. 2020;2 FSO644–2020-0128.

Schober et al., 2014 Schober M, Jesenofsky R, Faissner R, et al…. Desmoplasia and chemoresistance in pancreatic cancer. Cancers (Basel). 4 2014;2137–2154.

Setua et al., 2017 Setua S, Khan S, Doxtater K, Yallapu MM, Jaggi M, Chauhan SC. miR-145: Revival of a dragon in pancreatic cancer. Journal of Natural Sciences. 2017;3:e332.

Shang et al., 2019 Shang Q, Yang Z, Jia R, Ge S. The novel roles of circRNAs in human cancer. Molecular Cancer. 2019;1 6–018-0934-6.

Sharma et al., 2020 Sharma GG, Okada Y, Von Hoff D, Goel A. Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Seminars in Cancer Biology. 2020;S1044-579X.

Shaw et al., 2021 Shaw D, Chen H, Xie M, Jiang T. DeepLPI: A multimodal deep learning method for predicting the interactions between lncRNAs and protein isoforms. BMC Bioinformatics. 2021;1 24-020-03914-7.

Shekhani et al., 2013 Shekhani MT, Jayanthy AS, Maddodi N, Setaluri V. Cancer stem cells and tumor transdifferentiation: Implications for novel therapeutic strategies. American Journal of Stem Cells. 2013;1:52–61.

Shen et al., 2015 Shen Y, Pan Y, Xu L, et al…. Identifying microRNA-mRNA regulatory network in gemcitabine-resistant cells derived from human pancreatic cancer cells. Tumor Biology. 2015;6:4525–4534.

Shi et al., 2020 Shi H, Li H, Zhen T, Dong Y, Pei X, Zhang X. hsa_circ_001653 implicates in the development of pancreatic ductal adenocarcinoma by regulating microRNA-377-mediated HOXC6 axis. Molecular Therapy – Nucleic Acids. 2020;20:252–264.

Shi et al., 2019 Shi S, Jin Y, Song H, Chen X. MicroRNA-34a attenuates VEGF-mediated retinal angiogenesis via targeting Notch1. Biochemistry and Cell Biology. 2019;4:423–430.

Shimamura et al., 2020 Shimamura M, Nakagami H, Sanada F, Morishita R. Progress of gene therapy in cardiovascular disease. Hypertension. 2020;4:1038–1044.

Słotwiński et al., 2018 Słotwiński R, Lech G, Słotwińska SM. MicroRNAs in pancreatic cancer diagnosis and therapy. Central European Journal of Immunology. 2018;3:314–324.

Subramaniam et al., 2010 Subramaniam D, Ramalingam S, Houchen CW, Anant S. Cancer stem cells: A novel paradigm for cancer prevention and treatment. Mini-Reviews in Medicinal Chemistry. 2010;5:359–371.

Sun et al., 2018 Sun FB, Lin Y, Li SJ, Gao J, Han B, Zhang CS. MiR-210 knockdown promotes the development of pancreatic cancer via upregulating E2F3 expression. European Review for Medical and Pharmacological Sciences. 2018;24:8640–8648.

Sun et al., 2019 Sun J, Jiang Z, Li Y, Wang K, Chen X, Liu G. Downregulation of miR-21 inhibits the malignant phenotype of pancreatic cancer cells by targeting VHL. OncoTargets and Therapy. 2019;12:7215–7226.

Sun et al., 2020 Sun J, Russell CC, Scarlett CJ, McCluskey A. Small molecule inhibitors in pancreatic cancer. RSC Medicinal Chemistry. 2 2020;164–183.

Tang et al., 2017 Tang Y, Tang Y, Cheng YS. miR-34a inhibits pancreatic cancer progression through Snail1-mediated epithelial-mesenchymal transition and the Notch signaling pathway. Scientific Reports. 2017;7:38232.

Toscano-Garibay and Aquino-Jarquin, 2014 Toscano-Garibay JD, Aquino-Jarquin G. Transcriptional regulation mechanism mediated by miRNA-DNA*DNA triplex structure stabilized by Argonaute. Biochimica et Biophysica Acta. 2014;11:1079–1083.

Vila-Navarro et al., 2017 Vila-Navarro E, et al. MicroRNAs for detection of pancreatic neoplasia: Biomarker discovery by next-generation sequencing and validation in 2 independent cohorts. Annals of Surgery. 2017;6:1226–1234.

Vila-Navarro et al., 2019 Vila-Navarro E, Duran-Sanchon S, Vila-Casadesús M, et al…. Novel circulating miRNA signatures for early detection of pancreatic neoplasia. Clinical and Translational Gastroenterology. 2019;4:e00029.

Vychytilova-Faltejskova et al., 2015 Vychytilova-Faltejskova P, et al. MiR-21, miR-34a, miR-198 and miR-217 as diagnostic and prognostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma. Diagnostic Pathology. 2015;10 38-015-0272-6.

Waddell et al., 2015 Waddell N, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;7540:495–501.

Walsh et al., 2019 Walsh N, et al. Agnostic pathway/gene set analysis of genome-wide association data identifies associations for pancreatic cancer. Journal of the National Cancer Institute. 2019;6:557–567.

Wang et al., 2009 Wang J, Chen J, Chang P, et al…. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prevention Research (Phila). 2009;9:807–813.

Wang et al., 2019 Wang J, Guo J, Fan H. MiR-155 regulates the proliferation and apoptosis of pancreatic cancer cells through targeting SOCS3. European Review for Medical and Pharmacological Sciences. 2019;12:5168–5175.

Wang et al., 2019 Wang J, Zhu M, Pan J, Chen C, Xia S, Song Y. Circular RNAs: A rising star in respiratory diseases. Respiratory Research. 2019;1 3–018-0962-1.

Wang et al., 2011 Wang Z, Li Y, Ahmad A, et al. Pancreatic cancer: Understanding and overcoming chemoresistance. Nature Reviews Gastroenterology & Hepatology. 2011;1:27–33.

Watabe et al., 1998 Watabe T, Yoshida K, Shindoh M, et al…. The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. International Journal of Cancer. 1998;1:128–137.

Wei et al., 2011 Wei HJ, Yin T, Zhu Z, Shi PF, Tian Y, Wang CY. Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment. Hepatobiliary & Pancreatic Diseases International. 2011;4:428–434.

Weiss et al., 2009 Weiss FU, Marques IJ, Woltering JM, et al…. Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology. 2009;6 2136-45.e1–7.

Wong et al., 2020 Wong CH, Lou UK, Li Y, et al. CircFOXK2 promotes growth and metastasis of pancreatic ductal adenocarcinoma by complexing with RNA-binding proteins and sponging MiR-942. Cancer Research. 2020;11:2138–2149.

Wong et al., 2018 Wong WKM, Sorensen AE, Joglekar MV, Hardikar AA, Dalgaard LT. Non-coding RNA in pancreas and beta-cell development. Noncoding RNA. 2018;4 https://doi.org/10.3390/ncrna4040041.

Wu et al., 2020 Wu X, Huang J, Yang Z, et al. MicroRNA-221-3p is related to survival and promotes tumour progression in pancreatic cancer: A comprehensive study on functions and clinicopathological value. Cancer Cell International. 2020;20 443-020-01529-9. eCollection 2020.

Wu et al., 2021 Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D’Haese JG. The role of stellate cells in pancreatic ductal adenocarcinoma: Targeting perspectives. Frontiers in Oncology. 2021;10 621937.

Xie et al., 2018 Xie J, Wen JT, Xue XJ, Zhang KP, Wang XZ, Cheng HH. MiR-221 inhibits proliferation of pancreatic cancer cells via down regulation of SOCS3. European Review for Medical and Pharmacological Sciences. 2018;7:1914–1921.

Xing et al., 2019 Xing C, Ye H, Wang W, et al. Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression. Artificial Cells, Nanomedicine, and Biotechnology. 2019;1:3920–3928.

Xu et al., 2019 Xu Y, Yao Y, Gao P, Cui Y. Upregulated circular RNA circ_0030235 predicts unfavorable prognosis in pancreatic ductal adenocarcinoma and facilitates cell progression by sponging miR-1253 and miR-1294. Biochemical and Biophysical Research Communications. 2019;1:138–142.

Yang and Zeng, 2015 Yang J, Zeng Y. Identification of miRNA-mRNA crosstalk in pancreatic cancer by integrating transcriptome